Despite methadone's documented efficacy in achieving good treatment outcomes, many methadone maintained patients continue to use heroin during treatment. The goal of this component is to examine effects of i.v. heroin in patients maintained on methadone as well as interactions between methadone, cocaine and heroin in order to better understand the mechanisms that may underlie the continued use of heroin during methadone treatment. Four studies are proposed that utilize methods of the human behavioral pharmacology laboratory to perform systematic parametric investigations under controlled conditions. Study 1 examines reinforcing properties of i.v. heroin challenges, as indexed by subjective measures, at three methadone maintenance doses (30, 60, 120 mg/day) that include and surpass the range of doses in common clinical use and at three post-methadone dosing intervals (4, 28, 52 hours) that correspond to use of heroin on the same day as methadone is taken, on the following day prior to the scheduled methadone dose and following a missed methadone dose. Study 2 replicates and extends the results of study 1 by examining heroin's reinforcing properties, as indexed by i.v. heroin self-administration, at these same methadone maintenance doses. Study 3 determine whether use of heroin during methadone treatment engenders increased levels of physical dependence that must then be suppressed through additional heroin use. Signs and symptoms of physical dependence will be evaluated using both precipitated and spontaneous withdrawal methods in methadone maintained volunteers who are concurrently exposed to varying amounts of i.v. heroin use, under conditions that simulate patterns of supplemental heroin use in the natural environment. The use of heroin during methadone treatment is strongly associated with use of cocaine. Study 4 use subjective report methods to examine the reinforcing properties of heroin alone, cocaine alone and heroin-cocaine combinations in patients maintained on three methadone doses (30, 60, 120 mg/day). The aim is to determine whether and how cocaine's effects are modulated by concurrent use with heroin during methadone treatment. These four studies will provide empirical data on how various methadone doses influence the reinforcing properties of heroin when used alone or in combination with cocaine and will also illuminate conditions under which concurrent use of heroin adds to the physical dependence engendered by methadone maintenance. These studies will identify potential mechanisms underlying the continued use of heroin during methadone treatment and, because of their parametric nature, should suggest optimal treatment doses for minimizing heroin self-administration.